Methyl Effect in Azumamides Provides Insight Into Histone Deacetylase Inhibition by Macrocycles

Natural, nonribosomal cyclotetrapeptides have traditionally been a rich source of inspiration for design of potent histone deacetylase (HDAC) inhibitors. We recently disclosed the total synthesis and full HDAC profiling of the naturally occurring azumamides (J. Med. Chem. 2013, 56, 6512). In this work, we investigate the structural requirements for potent HDAC inhibition by macrocyclic peptides using the azumamides along with a series of unnatural analogues obtained through chemical synthesis. By solving solution NMR structures of selected macrocycles and combining these findings with molecular modeling, we pinpoint crucial enzyme–ligand interactions required for potent inhibition of HDAC3. Docking of additional natural products confirmed these features to be generally important. Combined with the structural conservation across HDACs 1–3, this suggests that while cyclotetrapeptides have provided potent and class-selective HDAC inhibitors, it will be challenging to distinguish between the three major class I deacetylases using these chemotypes.

天然非核糖体环四肽长期以来一直是开发强效组蛋白去乙酰化酶（HDAC）抑制剂的重要灵感源泉。我们团队近期报道了天然阿祖酰胺（azumamides）的全合成及其完整HDAC活性谱分析（J. Med. Chem. 2013, 56, 6512）。本研究以阿祖酰胺及其经化学合成得到的一系列非天然类似物为研究对象，探究大环肽类化合物强效抑制HDAC的结构必需特征。通过解析代表性大环肽的溶液态NMR结构，并将该结果与分子建模分析相结合，我们明确了强效抑制HDAC3所必需的关键酶-配体相互作用模式。对更多天然产物的分子对接验证证实，这些相互作用特征具有普遍适用性。结合HDAC 1-3之间的结构保守性，本研究提示：尽管环四肽类化合物已被用于开发强效且亚型选择性的HDAC抑制剂，但利用这类化学骨架区分I类HDAC家族的三种主要亚型仍颇具挑战。